2-(3-benzo(b)thenyl)-2-thiopseudourea and its pharmaceutically acceptable salts,compositions thereof and methods for using same

ABSTRACT

1. A PHARMACEUTICAL PREPARATION IN DOSAGE UNIT FROM ADAPTED FOR ADMINISTRATION TO OBTAIN SELECTIVE INHIBITION OF AGGRESSIVE BEHAVIOR COMPRISING AN ANTI-AGGRESSION-EFFECTIVE NON-TOXIC AMOUNT WITHIN THE RANGE FROM ABOUT 2 TO ABOUT 8 MG/KG. OF BODY WEIGHT OF A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THE BASE, 2-(3-BEZO(B) THENYL)-2THIOPSEUDORUREA, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF IN COMBINATION WITH A PHYSIOLOCALLY ACCEPATABLE CARRIER AND/OR DILUENT THEREFOR.

United States Patent 3,839,578 2-(3-BENZO(B) THENYL) 2 THIOPSEUDOUREAAND ITS PHARMACEUTICALLY ACCEPTABLE SALTS, COMPOSITIONS THEREOF ANDMETH- ODS FOR USING SAME Zaven S. Ariyan, Woodbury, Conn. 06798, andShih-Yu Ma, Cheshire, Conn. 06410 No Drawing. Original application Apr.6, 1972, Ser. No. 241,837. Divided and this application June 1, 1973,Ser. No. 365,873

Int. Cl. A61k 27/00 US. Cl. 424-275 18 Claims ABSTRACT OF THE DISCLOSURE2-(3-benzo(6)thenyl)-2-thiopseudourea and salts thereof in treatingaggressive behavior.

FIELD OF THE INVENTION pseudourea CH2 S (IL-:NH NH: s

and its pharmaceutically acceptable salts-novel compounds which havebeen found to be highly selective for the abolition of aggressivebehavior at doses which cause little or no signs or symptoms of centralnervous system depression or toxicity. The pharmaceutically acceptablesalts which have been tested, all of which appeared to have the activitymentioned above, include the chloride, bromide, benzoate, iodide,p-toluenesulfinate, p-toluenesulfonate and acetate. It is thought that,when taken orally, the salts may be buifered and the hydroxide or freebase formed. On the other hand, the acid pH of the stomach (around 2 inhumans) due to the presence of HCl is believed to cause reversion to thechloride, S-3-benz0[b] thenylisothiuronium chloride,

Therefore, much of the discussion of the invention hereinafter will bewith reference to the chloride. However, it will be understood that theinvention also encompasses the free base and other pharmaceuticallyacceptable salts thereof. In addition to the salts mentioned above,other suitable salts include the sulfate, nitrate, phosphate, maleate,fumarate, succinate, tartrate and citrate. Thus, while not wishing to bebound to any theory of how the compounds of the invention act in viva,it is also believed possible that the base is the pharmaceuticallyactive compound that is formed from the salts in animal tissue fluid.

It is well accepted in neuropharmacology that there is no cleardistinction between sedative-hypnotics and minor tranquilizers. Allknown minor tranquilizers which are effective in reducing anxiety alsoproduce drowziness, ataxia (inability to coordinate muscular movements)and "ice sleep when given in larger doses, All sedative-hypnotic drugsin small doses are anxiolytic (causing apprehension or anxiety).Sedative hypnotics such as alcohol and short-acting barbiturates tend toproduce behavioral excitation prior to promoting drowziness and sleep.The sedative hypnotics and minor tranquilizers produce discrete,predictable changes of behavior that can be applied to therapeuticadvantages in neurotics. Aside from their ability to promote sleep,their major behavioral actions of therapeutic advantage are theirabilities to slightly reduce the level of arousal-excitability, overcomepassive avoidance (social withdrawal, suppressed or submissive)behavior, slightly diminish aggressive hostility, and increase theresponse to environmental stimuli. The effect, for example, of apsychomimetic (inducing psychosislike symptoms) drug on animal behavior,such as LSD in rats and cats, has been said to increase excitement andaggression."

Currently, aggressive behavior in mental disease patients is usuallycontrolled by such major tranquilizers as chlorpromazine. This approachto the problem of controlling mental disorders is not entirelysatisfactory since patients under the influence of this type ofmedication are overtly depressed and not able to return satisfactorilyto society and to function normally. Chlorpromazine is a strong centralnervous system depressant, both in normal and schizophrenic patients.Its most salient feature, however, is the ability to inhibit aggressivebehavior in abusive and destructive schizophrenics. It has been the drugof choice for the treatment of so-called backward" schizoprenics, and isnow used in out-patient therapy in cases of simple schizophrenia. Thecompound has many side-effects, the most serious of which is that itcauses depression at the same time that it alleviates the schizophrenicsymptoms. Incidentally, it also has a disadvantage in that it is quitetoxic and has caused liver damage and blood disorders.

The abolition of aggressive behavior in schizophrenics withoutneurotoxicity as characterized by depression would be a most desirablefeature for a new drug in the therapy of mental disease. The compoundsof the present invention have been found to be agents which selectivelyblock aggressive behavior but do not cause depression.

Accordingly, in one respect, the invention is a method of treatingaggressive behavior. In another aspect, the invention is the compound2-(3-benzo[b]thenyl) 2 thiopseudourea and its pharmaceuticallyacceptable salts, and pharmaceutical compositions comprising thesecompounds. A particularly preferred compound of the pres ent inventionis S-3-benzo [b]thenylisothiuronium chloride.

The patent literature discloses many biologically activebenzo[b]thiophene compounds but does not disclose the particularcompounds of the present invention nor suggest the herein disclosedproperties thereof. For example, US. Pat. No. 2,916,495 to Edgertondiscloses a class of betathianaphthenylalkyl hydrazines as havingadvantageous hypotensive activity and the like; US. Pat. No. 3,010,971teaches that certain 2-(benzo-[b1-thenyl) cyclopropylamine derivativeshave the ability to act as antidepressive, ataractic and hypotensiveagents; British Patents Nos. 855,115 and 1,174,411 and US. Pat.3,070,606 disclose a number of benzo[b]thiophene derivatives as havingseveral pharmaceutical applications; and German Patent Publication No.1,937,514 (Feb. 19, 1970) discloses benzo[b]thiophenecarboxamides asbeing effective on the central nervous system, for example as havingantiemetic action against morphine or apomorphine. Moreover, US. Pat.No. 3,186,990 contains a generic disclosure which encompassesS-2-benzo[b]thenyl isothiuronium chloride, the 2-isomer of the chloridecompound of the present invention, and teaches that the class ofcompounds to which it relates are useful as fungicides. A similardisclosure is present in British Pat. No. 889,002.

3 In French Pat. 2,068,420, issued Aug. 27, 1971, 1-(benzo-[b]-3-thienyl-methyl) guanidine,

CH NE-C and its pharmaceutically acceptable salts, compounds which arestructurally closely related to those of the present invention, aredisclosed as being useful in the treatment of hypertension (higharterial blood pressure), hyperthyreosis (excessive functional activityof the thyroid gland) and tachycardia (relatively rapid heart action).It will be noted that the compounds of the French patent differ fromthose of the present invention by having an NH- radical substituted foran -S radical between the -CH and the on the side chain. However, as isknown, particularly in the pharmaceutical field, this difference is morethan enough to result in unanticipatable differences in properties.Indeed, such differences exist in the present case. Thus, although bothgroups of compounds are pharmaceuticals, their utilitie are in markedlydifferent and substantially unrelated pharmaceutical applications.

In addition, two U.S. Pats. Nos. 3,033,875 and 3,041,- 351, which relateto flavoring agents, contain identical descriptions of the preparationof 3-thionaphthylmethyl mercaptan. (Examples 3 and 2 of these patents,respectively.) As will become apparent from the description hereinafterof the preparation of the chloride compound of the present invention,the synthesis described in these two patents, more particularly atcolumn 2, lines 1-18 of U.S. Pat. No. 3,041,351 and column 3, lines35-43 of U.S. Pat. 3,033,875, follows a procedure similar to thatdescribed herein. However, the patentees reacted the resultingintermediate with NaOH; and they neither appreciated, identified norisolated the intermediate. Moreover, they teach a procedure whereby theintermediate is destroyed by treatment with aqueous sodium hydroxide.

The present invention provides a method of controlling aggressivebehavior in an animal subject without causing the central nervous systemdepression which is a typical side effect of drugs heretofore used totreat aggressive behavior. This is achieved by administering to ananimal subject a therapeutically effective amount of a compound selectedfrom the group consisting of 2-(3-benzo[b] thenyl)-2-thiopseudourea andits pharmaceutically acceptable salts, preferably S-3-'benzo[b]thenylisothiuronium chloride. Generally, the amount administered will be fromabout 1 to 50 mg./kg./day of body weight, preferably from about 2 to 8mg./kg./day.

The invention further provides as new compositions of matter,2-(Ii-benzo[b]thenyl)-2-thiopseudourea CHzS O and its pharmaceuticallyacceptable salts, which are effective as psychotherapeutic agents, moreparticularly as anti-aggression drugs, as well as pharmaceuticalcompositions comprising these compounds.

The salts of the present invention may be represented by the formula 4wherein Z is an anion derived from an acid which is pharmaceuticallyacceptable and whose pK value is between 0.4 and 6.5 and n is an integerfrom 1 to 3 equal to the charge on the anion. As indicated, the chloride(Z is Cland n is 1) is a particularly preferred salt.

The pharmaceutical compositions of the present invention comprise, incombination, a therapeutically effective amount of a compound of thepresent invention and a pharmaceutically acceptable carrier or diluenttherefor.

For example, in the case of a tablet, the composition will comprise, inaddition to the active ingredient, fillers, binders and diluents such aslactose, methylcellulose, talc, gum tragacanth, gum acacia, agar,polyvinylpyrrolidone, stearic acid and/or corn starch. In the case of aliquid suspension for oral administration, the composition willcomprise, in addition to the active ingredients, a filler such as sodiumcarboxymethylcellulose and/or a syrup, e.g. a glycerine based syrup. Inthe case of a parenteral solution or suspension, the composition willcomprise, in addition to the active ingredient, a suitabale liquidsolvent or dispersant such as a saline solution.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The compounds of the presentinvention may be obtained by conventional methods. Thus, S-3-benzo[b]thenyl isothiuronium chloride (A), is obtained from the reaction of3-chloromethyl-benzo[b]thiophene (C) with an excess of thiourea in awater-free organic solvent which is a solvent for thiourea. Absoluteethanol is the preferred solvent. Other suitable solvents includedioxane, acetonitrile and dimethyldiethylene glycol (Isothiuronium Thestarting reactant (C) was obtained from the chlorornethylation ofbenzo[b]thiophene. The other salts are obtained analogously. The freebase, 2-(3-benzo[b] thenyl)-2-thiopseudourea was obtained from thechloride by treatment with an aqueous sodium bicarbonate solution asfollows:

aqueous NaHC 0 The 2-isomer (B) of the chloride compound of the presentinvention was found to have none of the antiaggression activity shown bythe compounds of the present invention. The structure of the chloridecompound of the present invention is distinguished from its 2-isomer (B)on the basis of chemical evidence and physical data.

Chemically, the compounds are distinguished as follows. The hydrolysisof S-3-benzo [b]thenyl isothiuronium chloride (A) yielded3-benzo[b]thenyl mercaptan (D), which was characterized by N.M.R.(Nuclear Magnetic Resonance) spectroscopic analysis (See Example 3,Table II).

(A) (D) The hydrolysis of S-2-benzo[b]thenyl isothiuronium chloride (B)yielded 2-benzo[b]thenyl mercaptan (E), along with a small amount of2-benzo[b]thenyl disulfide The disulfide (F) is believed to be theproduct of the autoxidation of the mercaptan (E).

to] i S CHzSH S CHaSSCHfl s The 2- and 3-isomers were also distinguishedby the following physical data.

(1) S-3-benzo[b]thenyl isothiuronium chloride (A) has a melting point of222-224 C.

(2) S-2-benzo[b]thenyl isothiuronium chloride (B) has a melting point of194-6 C.

(3) The melting point of a mixture of (A) and (B) was 165-191 C.

(4) The N.M.R. spectral characteristics indicate existence of differentstructures (A) and (B). (See Tables I and II).

A sample of the 2-isomer (B) was prepared unequivocally via thefollowing synthetic scheme proceeding through the known intermediates(G), (H), and (I).

A. Preparation of 3-chloromethylbenzo[b]thiophene A modifiction of theprocedure reported by Blicke and Sheets [F. F. Blicke and Don G. Sheets,J. Am. Chem. Soc. 70 3768 (1948)] was used for the preparation of 3-chloromethylbenzo [b]thiophene by reacting benzo [b] thiophene withformaldehyde in an excess of concentrated hydrochloric acid as follows.

805 g. (5.65 moles) of benzo[b]-thiophene were added dropwise to astirred mixture of 3600 ml. of concentrated aqueous hydrochloric acidand 540 ml. of a 40% aqueous formalin solution at a temperature of about5 C. over a period of 3 hours. After stirring for 1 hour, the resultingpinkish mixture was heated to and held at 65 C. for 1 hour. Then thelower organic layer was separated. The aqueous layer was extracted withfour 800 ml. portions of benzene. The organic layer and the benzeneextracts were combined and then dried by passing through anhydrouspotassium carbonate and anhydrous sodium sulfate. Evaporation andfractional distillation through a Vigreux column afforded 831.7 g.(75.3%) of 3-chloromethylbenzo[b]thiophene, b.p. -132 C. (0.7-1.9 mm.),n 1.6440. [Lit. b.p. -127" C. (2.0 mm.)].

B. Preparation of S-3-benzo[b]thenyl isothiuronium chlorideS-3-benzo[b]thenyl isothiuronium chloride was prepared by the reactionof 3 chloromethylbenzo[b]thiophene with an excess of thiourea inabsolute ethanol as follows.

A sample of 91 g. (1.2 moles) of thiourea in 1500 ml. of absoluteethanol was heated to a temperature of 70 C. to obtain a clear solution.Then 109.9 g. (0.6 mole) of 3- chloromethylbenzo [b]thiophene were addeddropwise over a period of 15 minutes. The reaction mixture was thenheated under refluxing (83 C.) for 2 hours. On cooling (to an ambienttemperature of about 22 C. by stirring for about 30 minutes), acolorless solid weighing g. (84.5% yield) was deposited. It had amelting point of 213-217 C. Recrystallization from absolute ethanolafforded a colorless crystalline solid, m.p. 222.5- 224.5 C. (dec.); IR,

3160 cm." (broad), 2720 cm.- 1630 cmr 755 crnr N.M.R.

DMSO-do TMS I 4.92 (-CH S, singlet), 7.41 (Hg-l-H multiplet), 7.90 (Hsinglet), 7.99 (H.,+H multiplet), 9.46 (2NH broad singlet).

Analysis: Calculated for C H N S CI: C, 46.46; H, 4.28; N, 10.83; S,24.78. Found: C, 47.08, 46.82; H, 4.12, 4.45; N, 10.71, 10.64; S, 24.70,24.47.

C. Hydrolysis of S-3-benzo [b]theny1 isothiuronium chloride In order tofurther characterize the structure of S-3- benzo[b]-thenyl isothiuroniumchloride, it was hydrolyzed in the presence of sodium hydroxide to yield3- benzo[b]thenyl mercaptan as follows:

52 g. (0.2 mole) of S-3-benzo[b]thenyl isothiuronium chloride were addedto a solution of 28.6 g. of sodium hydroxide in 430 ml. of distilledwater at 45 C. The resulting mixture was then heated while stirring to99 C. and held at 99 C. for 4 hours, giving a clear yellow solution. 0ncooling to 15 C. (about 30 minutes), the solution was acidified withconcentrated aqueous hydrochloric acid. An organic layer was therebyformed and wasn then separated. The aqueous residue was extracted with700 ml. of ether in three portions. The organic layer and the etherextracts were combined and dried over anhydrous sodium sulfate.Evaporation and fractional distillation yielded 30.2 g. (83.8%) of acolorless liquid product, 3-thionaphthylmethyl mercaptan, which wascharacterized as follows, b.p. 104-109 C. (0.25-0.28 mm. Hg, n 1.6733[Lit. (US. Pat. 3,041,351 and Chemical Abstracts 57, 13729 [1962], b.p.156 C. (9.5 mm.)]; N.M.R.

1.54 (SH, triplet, J=7 cps), 3.72 (CH doublet, J=7 cps.), 7.07 (Hsinglet), 7.19 (H +H multiplet), 7.61 (Hm-H multiplet).

7 EXAMPLE 2 Preparation of 2-(3-benzo[b]LhenyD-Z-thiopseudourea Asuspension of 0.6 g. of S-3-benzo[b]theny1 isothiuronium chloride in 15ml. of water was chilled in an ice water bath. A aqueous sodiumbicarbonate solution was added dropwise until the pH of the solution wasabove 8. The insoluble product, weighing 0.57 g., was collected,dissolved in 8.0 ml. of ethyl acetate at 25 C. and filtered to removeinsoluble impurities. Upon cooling in an ice water bath, the2-(3-benzo[b]thenyl)-2-thiopseudourea product precipitated out ofsolution as a white solid. The yield was 0.4 g. of a product having amelting point of 105-l07 C. It was characterized as follows:

IR, x232 3400, 1620, 1580, 775 emf; N.M.R.

The decomposed sample has a melting range of 110 to 203 C. presumablybecause of the presence of dicyandiamide (m.p. 212 C.), which forms whencyanamide dimerizes.

CH; S C=NH CH: S H

+ HzNCEN 3-bcnzo[b]tl1eny1 mercaptan cyanamide EXAMPLE 3 A. Preparationof S-2-benzo [bJthenyl isothiuronium chloride As described below, asample of S-2-benzo[b]thenyl isothiuronium chloride was made by thereaction of 2-chloromethylbenzo[b]thiophene with thiourea. The starting2-chloromethylbenzo[b]thiophene was prepared via the unknownintermediates benzo[b]thiophene-2-carboxylic acid and2-hydroxymethyl-benzo[b]thiophene as herein above outlined schematicallybefore Example 1.

A yellow solution of 18.3 g. (0.1 mole) of2-chloromethylbenzo[b]thiophene in 70 ml. of benzene was added dropwiseover a period of 80 minutes to a sample of 15.2 g. (0.2 mole) ofthiourea in a mixed solvent of 150 ml. of absolute ethanol and 100 ml.of benzene. An exotherm from 25 C. to 28 C. occurred. The reactionmixture was then refluxed for 2 hours. Evaporation yielded a wet,yellow, solid residue. After stirring with 100 ml. of petroleum etherfor about minutes, filtration yielded 34 g. of a light yellow solidproduct having a melting point of 140-l56 C. A sample of 25.7 g. of thecrude reaction product was stirred at room temperature with 230 ml. ofacetonitrile in two portions to yield 14.6 g. of a pale yellow solidhaving a melting point of 184188 C. An analytical sample having amelting point of 194- 196 C. was prepared by dissolving 0.55 g. of thisproduct in 75 ml. of water at 65 C., filtering and reprecipitating withconcentrated aqueous hydrochloric acid. The product, S-2-benzo[b]thenylisothiuronium chloride, was characterized as follows:

JZEE.

8 3150 cm." (broad), 2720 cmr 1650 cm.- 750 cmr N.M.R. a Qg 4.98 (CH S-,singlet), 7.34 (H +H multiplet), 7.48 (H singlet), 7.85 (H +Hmultiplet), 9.45 (2NH broad singlet).

Analysis: Calculated for C H N S Cl: C, 46.46; H, 4.28; N, 10.83; S,24.78; Cl, 13.70. Found: C, 46.49, 46.28; H, 4.43, 4.52; N, 10.30,10.28; S, 22.40, 26.93; Cl, 13.48, 13.86.

B. Hydrolysis of S-2-benzo[b]thenyl isothiuronium chloride In order todifierentiate between the corresponding 2- and 3-S-benzo[b]thenylisothiuronium chloride isomers, S-2-benzo[b]thenyl isothiuroniumchloride was hydrolyzed to 2-benzo[b]thenyl mercaptan, a solid product,as follows: 14.6 g. (0.057 mole) of 2-benzo[b]thenyl isothiuroniumchloride were added to a solution of 6.4 g. of sodium hydroxide in ml.of water having a temperature of 25 C. An exotherm to 34 C. occurred.After 15 minutes, the reaction mixture was then heated to and held at 98C. for 4 /2 hours, giving a yellow solution containing some insolublematerial. This solution was then diluted with 200 ml. of water, cooledto a temperature of 15 C. with an ice water bath and acidified withconcentrated aqueous hydrochloric acid. The aqueous solution was thenextracted with 1000 ml. of benzene in four portions. The yellow benzeneextract was washed with water and saturated sodium chloride solution,and then dried over anhydrous sodium sulfate. Evaporation yielded 9.5 g.(100% yield) of a yellow, wet, solid product.

A sample of 4.0 g. of this crude product was chromatographed on silicagel (230 g.), using a cyclohexane-benzene mixture (4:1) for elution.Evaporation of the first main fraction yielded 1.06 g. of pale yellowcrystalline plates of 2-benzo[b]theny1 mercaptan, which had thefollowing characteristics,

Melting point, 50-5 1 C. (from cyclohexane);

IR xfigif 2550 cmf 740 em.' N.M.R. agfg 1.81

(-SH, triplet, I =8 cps), 3.93 (-CH doublet, 1:8 cps.), 7.08 (H;,,singlet), 7.14 (H +H multiplet), 7.61 (Hg-i-Hq, multiplet).

Analysis: Calculated for C H S C, 59.96; H, 4.47; S, 35.57. Found: C,59.90, 59.74; H, 4.49, 4.42.

Evaporation of the second main fraction yielded 0.1 g. of colorlesscrystalline plates of 2-benzo[b]thenyl disulfide, which had thefollowing characteristics. Melting point, 131-132 C. (from ethylacetate);

IR @33 480 emf; N.M.R. 53 3 9307 (CH singlet), 7.10 (H singlet), 7.29 (H-l-H multiplet), 7.73 (Hg-H multiplct).

Analysis: Calculated for C H S C, 60.30; H, 3.94; S, 35.77. Found: C,60.06, 60.04; H, 3.96, 4.00; S, 34.70, 34.39.

The chemical evidence, physical data and biological activity of both 3-and 2-S-benzo[b]thenyl isothiuronium chloride, which are summarizedbelow, show that the structure of the chloride compound of thisinvention is the 3-isomer of S-benzo [b]thenyl isothiuronium chloride:

S-3-benzo[b]thenyl isothiuronium chloride:

Melting Point: ZZZ-224 C.

Mixed melting point with 2-isomer: -191 C.

infrared spectrum: similar to that of the 2-isomer N.M.R. spectrum: ForH 6=7.90 (see Table I) Hydrolysis product: 3-benzo[b]thenyl mercaptan, aliquid; boiling point 104-109 C. (0.28-0.25 mm.); n 1.6733, N.M.R. (seeTable II) for H 6:7.7 singlet, SH, 6:1.54 triplet. Biological activity:Active as an antiaggression drug.

9 S-2-benzo[b]thenyl isothiuronium chloride:

M.p.: 194-196 C.

Mixed m.p. with 3-isomer: 165-191 C.

Infrared spectrum: similar to that of the 3-isomer N.M.R. spectrum: ForH 6 7.48 (see Table I) Hydrolysis product: 2-benzo[b]thenyl mercaptan, asolid, m.p.: 50-51 C. N.M.R. (see Table II) for H 6:7.08 singlet, SH,6:1.81 triplet. Biological activity: Inactive as an antiaggression drug.

TABLE I N.M.R. spectral properties of 3 and 2-S-benzo[b]thenylisothiuronium chloride A. Preparation of 3-bromomethylbenzo [b]thiopheneTo a stirred mixture of 400 ml. of 40% aqueous hydrobromic acid and 60ml. of 40% aqueous formaldehyde at 6 C. were added, dropwise, 80 g. (0.6mole) of benzo[b]thiophene over a period of 20 minutes. After stirringfor 1 hour, the reaction mixture was heated and held at 65 C. for onehour and then chilled to 15 C., followed by the addition of 500 ml. ofice water, and then extracted with 900 ml. of benzene in three portions.The extracts were combined and dried by passing through anhydrouspotassium carbonate and anhydrous sodium sulfate. Evaporation on a steambath yielded 136 g. of a dark brown crude liquid product. Fractionaldistillation removed 9.5 g. of low-boiling material. The higher boilingreisdue, 3 bromomethylbenzo[b1thiophene, weighed 95 g. (70% yield).

B. Preparation of S-3-benzo b]thenyl isothiuronium bromide 95 g. of the3-bromobenzo [b] thiophene prepared above was suspended in 200 ml. ofabsolute ethanol and added to a refluxing solution (80 C.) of 64 g.(0.84 mole) of thiourea in 600 ml. of absolute ethanol. Reflux wascontinued for two hours, and the resultant dark brown solution was thenallowed to cool to room temperature and filtered to remove a traceamount of insoluble material. Evaporation of the filtrate yielded 122.4g. of a pale yellow solid product, m.p. 138-168 C. Trituration of thecrude product in 125 ml. of acetone yielded 65 g. (51% yield) of theproduct, S-3-benzo[b]thenylisothiuronium bromide, m.p. 205-210 C. Ananalytical sample, m.p. 207-209 C., was prepared by dissolving 1.0 g. ofthe product in 25 ml. of absolute ethanol and 1.0 ml. of water andreprecipitating with the addition of 40% aqueous hydrobromic acid. Itwas characterized as follows:

IR, 1 1539 3250 cm? (broad), 3100 cmf 1035 cmf 755 om.' N.M.R. 59 1, 55.02

(CH S, singlet), 7.45 (H -l-H multiplet), 8.00

H2+H4+H7, multiplet), 9.35 (2NH broad singlet).

Analysis: Calculated for CIOHHBI'NZSZ (percent): C,

39.61; H, 3.66; Br, 26.35; N, 9.24; S, 21.15. 'Found (per- 10 cent): C,38.76, 39.01; H, 3.79, 3.79; Br, 24.60, 24.58; N, 8.71, 8.83; S, 20.3,20.1.

'EXAMPLE 5 Preparation of SF3-'benzo [b]thenyl isothiuronium iodide Amixture of 12.9 g. (0.05 mole) of S-3-benzo[b] thenyl isothiuroniumchloride and 45 g. (0.3 mole) of sodium iodide in 1000 ml. of acetonewas heated under reflux (55 C.) for 29 hours, resulting in a yellowsolution with a trace of precipitate. Filtration removed 3.2 g. of awhite solid. Evaporation of the filtrate gave 72.4 g. of a pale yellowresidue. The residue was stirred with 61 ml. of water and filtered anddried to yield 22 g. of crude S-3-benzo [b]isothiuronium iodide, mp.167-- 172 C. Recrystallization from 23/77% ethanol/H O solution andrinsing with ethyl acetate afforded a colorless analytical sample, m.p.173-174 C., which was characterized as follows:

IR, @319 3300 emf, 3100 cmf 1510 emf- 755 cm.";

0 N.M.R. 5. 2 1

4.85 (-CH S-, singlet), 7.45 (H +H multiplet), 7.86 (H singlet), 8.02(Hr-l-Hq, multiplet), 9.09 (ZNH broad singlet).

Analysis: Calculated for C H N S I (percent): C, 34.29; H, 3.16; 'N,8.00; S, 18.31; I, 36.24. Found (percent): C, 34.56; 34.58; H, 3.25,3.14; N, 8.16, 8.25; S, 17.42, 17.44; I, 37.44, 37.22.

EXAMPLE 6 Preparation of S-3-benzo[b]thenyl isothiuronium acetate To asolution of 0.5 g. (0.006 mole) of sodium acetate in 5.0 ml. of water, asuspension of 1.0 g. (0.0039 mole) of S-3-benzo[b]thenyl isothiuroniumchloride in 10 ml. of absolute ethanol and 1.0 ml. of water at 50 C. wasadded. The clear reaction solution was heated on a hot water bath for 5minutes. On cooling, it yielded 0.89 g. (82% yield) of a colorless solidproduct, S 3-benzo[b] thenylisothiuronium acetate, m.p. 148-150 C.,which was characterized as follows:

IR, 153,19 3400 cmf 1030 cm.- 1550 cat- 760 cmr N.M.R. a 1.76

((EHaL JO- singlet),

4.60 (CH S, singlet), 7.96

(HQ-H multiplet), 8.26 (2NH broad singlet), 7.75 (H singlet), 7.41 (H +Hmultiplet).

Analysis: Calculated for C H N O 'S (percent): C, 51.04; H, 5.00; N,9.93; S, 22.71. Found (percent): C, 50.94, 50.94; H, 5.32, 5.21; N,9.45, 9.51; S, 22.96, 22.96.

EXAMPLE 7 Preparation of S-3-benzo[b]thenyl isothiuronium benzoate To asolution of 0.87 g. (0.006 mole) of sodium benzoate in 7 ml. of water, asuspension of 1.0 g. (0.0039 mole) of S-3-benzo[b]thenyl isothiuroniumchloride in 10 ml. of absolute ethanol and 1.0 ml. of water at 50 C. wasadded. As a white precipitate was formed immediately, an additional 20ml. of water was added. The resulting mixture was then heated at 65 C.for 10 minutes. Filtration yielded 1.47 g. yield) of a white solid,S-3-benzo- [b]thenyl isothiuronium benzoate, m.p. 175-176 C. Re-

IR, Nujol 3200 cm.- (broad), 1590 cmf 1250 emf,

(-CH S--, singlet), 6.80 (2NH broad singlet), two multiplets centered at7.45 and 7.90 for the aromatic protons.

Analysis: Calculated for C H N O S (percent): C, 59.38; H, 4.68; N,8.13; S, 18.62. Found (percent): C, 56.33, 56.33; H, 4.49, 4.61; N,8.49, 8.49; S, 19.51, 19.52.

EXAMPLE 8 Preparation of S-3-benzo[b]thenyl isothiuroniump-toluenesulfinate A sample of 0.5 g. (0.028 mole) of sodiump-toluenesulfinate in 5.0 ml. of water was warmed on a water bath togive a clear solution. To this aqueous solution of sodiump-toluenesulfinate, a suspension of 1.0 g. (0.0039 mole) ofS-3-benzo[b]thenyl isothiuronium chloride in 10 ml. of absolute ethanoland 1.0 ml. of water at 50 C. was added. The resulting mixture washeated at 65 C .for 58 minutes. On cooling, 0.91 g. (63% yield) of acolorless, solid product, S-3-benzo[b]thenyl isothiuronium ptoluenesulfinate, was obtained. Recrystallization from an ethanol-water mixtureafforded an analytical sample, m.p. 168169 C., which was characterizedas follows:

IR, $319 3200 cmf 1670 emf, 750 emf; N.M.R. 6 5, 2.30

(@CH|, singlet 4.70 (CH S, singlet), 7.16

- ,S@Me, doublet 7.42

028- --Me and He H1. doublet 7.95 (H.,+H multiplet), 9.90 (2NH, broadsinglet), 7.77 (H singlet).

Analysis: Calculated for C H N O S (percent): C, 53.94; H, 4.80; N,7.40; S, 25.41. Found (percent): C, 52.61, 52.79; H, 5.15, 5.06; N,7.08, 7.12; S, 2439, 24.24.

EXAMPLE 9 Preparation of S-3-benzo[b]thenyl isothiuroniump-toluene-sulfonate IR, @319 3200 cm., 1660 cmr 1200 emf, 1030 emr 775emf; N.M.R. 6955 2.28

(@0 H1, singlet Me, doublet 7.48

0.s--M0, H4 11,, multlplet 7.81 (H singlet), 7.98 (H.,+H multiplet),9.17 (ZNH broad singlet).

Analysis: Calculated for c qH 3N2O3S3 (percent): C, 51.75; H, 4.60; N,7.10; S, 24.35. Found (percent): C, 52.45, 52.33; H, 4.84, 4.83; N,7.11, 7.09; S, 24.53, 24.36.

The most outstanding property of the compounds of the present invention,and particularly the chloride, S-3- benzo[b]thenyl isothiuroniumchloride, is the highly selective abolition of aggressive behavior indoses which cause little or no signs or symtoms of central nervoussystem depression or toxicity. The compounds can be classified aspsychotherapeutic agents, but are unique in that no other agent of thisclass possesses the same spectrum of activity. The compounds of thepresent invention have neuropharmacological profiles in mice whichresemble those of the major tranquilizers such as chlorpromazine. Theydiffer from chlorpromazine, however, in that they are much weakerdepressants of motor activity in the mouse. The compounds of Examples10-16 of Table III below, in addition to having positiveneuropharmacological profiles, all gave protection in the isolatedfighting mouse assay. In particular, S-3-benzo[b]thenyl isothiuroniumchloride was very active in inhibiting aggressive behavior in threemodels of experimental aggression; namely, isolated fighting behavior inmice, electroshock-induced fighting in mice, and septal rat aggression.In a comparative study with a major tranquilizer, chlorpromazine, and aminor tranquilizer, chlordiazepoxide, the chloride of the presentinvention was found to be much more selective in inhibiting aggressivebehavior than the latter two agents. It does not possess significantanti-convulsant activity and in this respect it differs fromchlordiazepoxide. It does, however, cause a significant hypothermia,which indicates an activity resembling chlorpromazine and other majortranquilizers. It is a weak potentiator of pentobarbital and is inactivein the dl-dopa fighting test for monoamine oxidase inhibitors. Itapparently does not possess antidepressant activity since it did notreverse tetrabenazine ptosis. The chloride of the present invention isorally active in mice and rats and orally is less toxic thanchlorpromazine and chlordiazepoxide. By contrast with the chloride ofthe present invention, S-3-benzo[b]thenyl isothiuronium chloride, its2-isorner, S-2-benzo[b]thenyl isothiuronium chloride had no activity asan antiaggression drug.

Table III lists, in addition to compounds of the present invention(Examples 1016), fourteen related compounds, including the 2-isomer ofthe chloride (Example 29), whiclh were tested for similar activity butwith negative resu ts.

The neuropharmacological profile is a standard procedure (see, e.g.Samuel Irwin, Science, 136, 123 [1962]) employed in screening a compoundto determine its usefulness as a Central Nervous System active compound.When a compound is found to have sutficient activity to warrantfollow-up, the {irstanmggresslon screen, the fighting mouse assay, isdeermine TABLE IIL-NEUROPHARMACOLOGICAL PROFILE F I s N Example No. 1; RR Pharm, ofil 1 NHz H e --CHr-S-C 01 11 NH:EB H

-oHls-o m 12 NHf H e -cHis -c o 0 0 13 NHI$ H oHis-o 1 14 NH; H e-oH,-s-c Hie- -s o,

15 NILG3 H e -oH,-s-c Hios 0.

1 NHi H -cHis-o CHQCOOG H -o o 0151; -0H,01 H CH1CH2C 0 OH H -oH,-cHo00Et H oHi-cmoooH HCH OH m n -OEt H 2 yp -CHSPh H -CH1Cl H H S0zPh(pMe)H -CHzOHiOI-I H -oH,-s-

29 H NH? (Hypnotic) & e --cHi-s-o 01 30... -oH,-sH H No'rE.--+++indicates active; -indicates inactive; +indicates weakly active.

Example 23 is the 2:3-dihydro derivative; Example 29 is the 2-benzo[b]chloride isomer, which showed some CNS depressant activity in theneuropharmacological profile with mild hypnotic activity. In furtherhypnotic assays this compound proved inactive and, more important, wasinactive in the isolated fighting mouse and the septal rat tests. Bycontrast, its 3-isomer (the chloride of the present invention [Example10]) was very active in the latter two tests, which are diagnostic testsfor antiaggression activity.

In the neuropharmacological profile, which is a standardizedmultidimensional observation technique used on mice to gradesymptomatology and acute toxicity relative to dosage, the S-3-benzo[b]thenyl isothiuronium chloride compound of the present inventioncaused convulsions and/or death after intraperitoneal doses of 300 and100 mg./kg. After doses of 30, 10, and 3 mg./kg., depression,hypothermia, hypoand hyper-reflexia, reduced motor activity, and somedegree of catatonia were observed. Depending upon the dose used, theonset of action varied from 4 to 30 minutes.

Similar observations were noticed after oral administration of thiscompound, except that no convulsions were observed at the 300 rug/kg.dose. In addition, the onset of action was longer, ranging from 15 to 60minutes. These observations indicate a lesser degree of absorptionfollowing oral administration as compared to intraperitoneal dosing.

S-3-benzo [b]thenyl isothiuronium chloride and two commonly usedtranquilizers were subjected to the spontaneous locomotor activity test,in which six mice or rats per dose were placed in individual photocellactivity cages 3-0 minutes (mice) or 60 minutes (rats) after i.p.(intraperitoneal) administration of the drug for a 30 minute activitycount. Table IV shows the results obtained by comparing drug-treatedgroups with control activity, the

TABLE IV Bpontaenous Locomotor Activity LP. SD50 (mg/kg.)

Mice Rats S-3-benzolb1thcnyl isothiuronium chloride chlorpromazine..."

Chlordiazepoxide S-3-benzo[b]thenyl isothiuronium chloride appears topossess a much weaker depressant action in both mice and rats incomparison with chlorpromazine (major tranquilizer) and chlordiazepoxide(minor tranquilizer).

In addition, S-3-benzo[b]thenyl isothiuronium chloride exhibiteddepressant activity when given orally, with an SD of 85.5 mg./kg. inmice and greater than 200 mg./kg. in rats.

In the neurotoxicity test, the value NTD is defined as the dosenecessary to cause 50% of mice or rats trained to walk a rotating woodenrod (5 r.p.m.) to fall at the time of peak effect, and is a measure ofdrug eifects on motor function or central nervous system toxicity. Theresults set forth in Table V were obtained when S-3-benzo- [b]thenylisothiuronium chloride was tested against chlorpromazine andchlordiazepoxide.

TABLE V.--NEUROTOXICITY p S-3-benzolb1thenyl isothiuronium chloride..

Chlorpromazine. Chlerdiazepoxide P.O.: i S-3-benzolb1thenylisothiuronium chloride l Intraperitoneal. I Oral (Per 0s).

The time of peak effect for each agent in both species was 15-30 minutesafter drug administration.

Again, S-3-benzo [b]thenyl isothiuronium chloride was less potent thaneither reference drug. In addition, S-3- benzo[b]thenyl isothiuroniumchloride appeared to be more centrally toixc in rats than in mice.

This compound was also compared with chloropromazine andchlordiazepoxide for its anti-aggressive activity. Four models ofexperimentally-induced aggression in rodents were studied (R. D. Sofia,Life Sciences 8: 705, 1969). The results of these experiments aresummarized in Table VI.

The results of this study indicate that the S-3-benzo[b]- thenylisothiuronium chloride compound of the present invention possessesselective anti-aggressive activity against isolation-induced aggressionand septal rat aggression, which no standard psychotherapeutic agentpossesses. In comparison with chlorpromazine and chlordiazepoxide, usingthe ratio between NTD and ED in these models, S-3-benzo[b]thenylisothiuronium chloride possesses a high degree of specificity incombating experimentally-induced aggressive behavior. Drug specificityon these studies was considered selective only when it occurred at doseswhich were significantly lower than those which impaired rotarodperformance (NTD or resulted in a ratio (NTD /ED of greater than 1.0.

Electroshock-induced fighting is a test procedure that selectivelydepicts anti-anxiety activity. This fact was shown sincechlordiazepoxide was quite active.

Killer rat aggression appears to be a test which selectively indicatesanti-depressant and stimulant activity since reference agents from boththese classes of drugs are selectively active (R. D. Sofia, LifeSciences, 8: 120, 1969). None of the drugs tested selectively inhibitedkiller rat behavior.

chlorpromazine was able to block all types of aggressive behavior, butonly after doses which caused neurotoxicity, which is expected of thismajor tranquilizer.

Hence, S-3-benzo[b] thenyl isothiuronium chloride differs from bothchlorpromazine and chlordiazepoxide in that it selectively inhibitsseptal rat aggression and isolated mouse aggression at doses well belowthose causing signs of neurotoxicity. In addition, this degree ofselectivity of S-3-benzo[b]thenyl isothiuronium chloride foranti-aggressive activity is further supported by the fact that it isquite active at doses well below doses inhibiting spontaneous locomotoractivity.

TABLE VI.ANTI-AGGRESSIVE ACTIVITY ED confidence limits) (mg/kg.)

i.p. P.O.

NTDso/ NTD Agent ED ED. no.0 E1524 Isolated mouse aggressionB-3-benzo[b]thenyl isothiuronium chloride 2.6 (1. 0-6. 7) 60.0 8.3 (4.6-15. 2) 10.0 Chlorpromazine 2.8 (2.0-3.9) 0.3 6.9 (5.1-9.4) 1.7Chlordiazepoxide. ..-20.5 (11.3-37.5) 0.7 35.0 (25. 4-48. 3) 1.5

Eleetroshoek-induced fighting in mice S-3-benzo[b]thenyl isothiuroniumchloride Weakly active chlorpromazine 5. (3. 1-9. 9) 0.1 0.86(0.39-1.88) 14.0 Ohlordtazep0x1de.-... 4.2 (2.3-7.7) 3.3 3.0 (1. 7-5. 4)18.0

Septal rat aggression S-3-benzo[b]thenyl isothiuronium chloride 7.0 (3.9-12. 7) 5.1 4.2 (2.3-7.8) 72.0 chlorpromazine 10.7 (4. 5-25.7) 0.2 11.4(6.1-21.4) 0.9 Chlordiazepoxide 25.8 (14.0-47.5) 0.4 23.7 (13.0-59.0)0.49

Killer rat aggression S-3-benzo[b]thenyl isothiuronium chloride 47.0(38.9-57.0) 0.8 chlorpromazine 7.2 (4. 3-11. 8) 0.2 17.4 (10. -29.8) 0.6Chlordiazepoxide. 36.3 (24.2-54.4) 0.3 74 0 (531-1028) 0. 15

Anticonvulsant activity was tested in the following procedures.

1. Maximal Electroshock Seizures (MES TABLE VII Maximal electroshockseizures Agent I.p. MES mg./kg.

S-3-benzo[b]thenyl isothiuronium chloride 125. Chlorpromazine In ctive(25 mg./kg.). Chlordiazepoxide 41.5 (37.8-35.6).

S-3-benzo[b] thenyl isothiuronium chloride is much less potent thanchlordiazepoxide in protecting against MES but difiers fromchlorpromazine in that the latter is completely devoid of activity.

2. Pentylenetetrazol Seizures (MET TABLE VIII Pentylenetetrazol seizuresAgent I.p. MET rug/kg.

S-Ii-bgififibkhenfl isothiuronium Inactive (100 ing/kg). ChlorpromazineInactive (100 ing/kg). Chlordiazepoxide 7.1 (5.6-90) for convulsions.

2.6 (2.2-3.1) for death.

f the drugs tested, only chlordiazepoxide exhibitedanti-pentylenetetrazol activity.

d-Amphetamine Aggregation Protection from d-amphetamineaggregation-induced lethality is usually afforded byalpha-adrenergic-blocking agents such as chlorpromazine,penoxybenzamine, etc. Percent protection was determined for eachcompound and an ED value calculated. The results are summarized in TableIX.

TABLE IX d-Amphetamine aggregation Agent EDsomgJkg.

S-3-benzo[b]thenyl isothiuronium chloride... 50 rug/kg. Ohloropromazine1.2 (0.8-1.8) ing/kg. chlordiazepoxide Inactive (50mg./kg.).

In this test procedure, S-3-benzo [b]thenyl isothiuronium chloride hasapproximately l/40th the potency of chlorpromazine, whilechlordiazepoxide is completely inactive. Therefore, the chloride of thepresent invention can be considered to possess very weakalpha-adrenergic blocking activity.

Drug Interaction Studies S-3-benzo [b]thenyl isothiuronium chloride,chlorpromazine, and chlordiazepoxide were compared in the following druginteraction studies.

1. Pentobarbital TAB LE X Percent increase in control sleep timeS-3-benzo[b]thenyl isothiuronium I.p. dose mgJkg. chloride chlordia-Chlorprozepoxide mazine On a dose to dose relationship, S-3-benzo[b]thenyl isothiuronium chloride appears to have approximately 1/ 20ththe potency of chlorpromazine. That is, it requires about 20 times asmuch of S-3-benzo[b]thenyl isothiuronium chloride as of chlorpromazineto achieve the same potency. On the other hand, at the same dosage, 10mg./kg., S-3- benzo[b]thenyl isothiuronium chloride has approximatelytwo to three times more potency than chlordiazepoxide. Therefore, thiscompound of the present invention shows potentiation of barbiturateanesthesia.

2. Dihydroxyphenylalanine (dl-DOPA) Fighting Test It is well known thatwhen monamine oxidase (MAO) inhibitors are given prior to thenoradrenaline precursor, dl-DOPA, convulsions or excitation occur. Inthis study, the MAO inhibitor, pargyline mg./kg.), was given 1, 2, and 4hours prior to administering 200 mg./kg. of dl-DOPA. Results of thisexperiment are manfested by excitation, salivation, jumping, andfighting. When S-S- benzo[b]thenyl isothiuronium chloride (60 mg./kg.),chlorpromazine (5 mg./kg.), or chlordiazepoxide (15 mg./ kg.) wereadminstered instead of pargyline, these symptoms were not observed.Thus, in this procedure, none of the agents tested appear to be MAOinhibitors.

3. Yohimbine Potentiation Potentiation of lethality induced by thealpha-adrenergic blocking agent, yohimbine, is considered by someinvestigators as a reliable procedure to classify possibleantidepressant compounds (R. M. Quinton, Brit. J. PharmacoL, 21: 51,1963). An ED in this test is defined as that dose of test drug whichwill cause the LD, (25 mg./ kg. i.p.) of yohimbine to be converted tothe LD value. Groups of ten mice each are placed in a tote box and areinjected with vehicle or test drug. Thirty minutes later each mouse isinjected i.p. with yohimbine at 25 mg./kg. Sixty minutes followingyohimbine administration, the number of deaths in each tote box for eachdose of test drug is recorded. (Vehicle-treated mice should have none orone of ten mice dead.) Neither chlorpromazine (10 mg./kg.) norchlordiazepoxide (20 mg./kg.) was active in this test. However,S-3-benzo [b]-thenyl isothiuronium chloride resulted in an ED value of54.2 mg./kg. (292-1015). Since S-3-benzo[b]thenyl isothiuronium chloridewas not selectively active in the killer rat aggression test, whichappears to detect antidepressant activity, it is possible that thisagent might possess weak antidepressant activity at doses which causesneuro toxicity. Hence, a third test for detection of antidepressantactivity was conducted.

4. Antagonism of Tetrabenazine-induced Ptosis Groups of mice were given32 mg./kg. of tetrabenazine intraperitoneally 30 minutes after aninjection of S-3- benzo [b]thenyl isothiuronium chloride (30 mg./kg.).The degree of ptosis (eyelid drooping or closure) was then determinedexactly 30 minutes after tetrabenazine admin istration.S-3-benzo[b]thenyl isothiuronium chloride did not reversetetrabenazine-induced ptosis as do the antidepressants desipramine andamitriptyline.

5. Oxotremorine Antagonism Antagonism of the pharmacological effects of0x0- tremorine, a potent cholinergic stimulant, was studied in miceafter intraperitoneal administration of SF3-benzo [b] thenylisothiuronium chloride mg./kg.). (F. Sjoquist and I. Gillette, Life.Sci., 4: 1031, 1965). In this test, groups of ten mice are individuallyplaced into plexiglas squares. Mice are injected i.p. with the vehicleor test drug thirty minutes prior to an i.p. injection of 0x0- tremorineat 0.5 mg./kg. Immediately following oxotremorine administration, themice are observed for salivation and tremors. Peripheral anticholinergicactivity is assessed by inhibition of salivation, and central activityby inhibition of tremors. At 100 mg./kg., S-3-benzo [b] thenylisothiuronium chloride was completely devoid of any anticholinergicactivity.

19 6. Lethality Study TABLE XI LD 1 (95% confidence limits) mgJkg.

Mice

Rats

Agent P.O. P.O.

S-3-benzo[b]theny1 isothiuronium chloride.

Chlorpromazine Chlordiazepoxide 400 810 265 (265-604) (688-958)(224-313) These data show that S-3-benzo[b]thenyl isothiuronium chlorideis much less toxic in mice than in rats when administeredintraperitoneally and that it is much less toxic for both methods ofadministration in mice and when orally administered to rats whencompared to the two standard reference drugs.

The compounds of the present invention, either alone or in the form of apharmaceutical composition, may be administered to an animal subject inany of a number of forms and via any of several routes. Thus, thecompounds or compositions thereof may be orally administered in the formof tablets, pills, capsules or in the form of a solution or liquidsuspension. They may also be administered in the form of a parenteralsuspension or solution. The compounds or compositions thereof may alsobe administered rectally, in the form of a suppository.

When orally administering the compounds or compositions, use can be madeof a tablet, pill or capsule consisting entirely of the desiredcompound, although ordinarily, a composition comprising an effectiveamount of the compound and varying amounts of one or morephysiologically inert materials such as carriers, vehicles, binders andthe like will be used. Additionally, the compounds may be orallyadministered in the form of a suspension thereof in a suitable vehiclesuch as a syrup.

When parenterally administering the compounds or compositions, use maybe made of a parenteral solution or suspension thereof in a suitablesolvent or suspension medium.

The compounds and compositions of the present invention may also beadministered rectally in the form of a suppository comprising aneffective amount of the desired compound and a suitable vehicle such aspetroleum jelly.

The following examples are specific formulations of compositions inaccordance with the invention.

EXAMPLE 31 Tablets may be prepared by the compression of a wetgranulation containing the following:

Ingredients: In each S-3-benzo [bJthenyl isothiuronium chloridePolyvinylpyrrolidone mg 6 Lactose mg 25 Alcohol, 3A, 200 proof ml 1Stearic acid mg 3 Talc mg 4' Corn starch mg Dosage: 1 Tablet 3 times aday.

EXAMPLE 32 A liquid suspension for oral administration may be preparedin the following formulation:

Ingredients: In each 5 cc.

S-3-benzo[b]thenyl isothiuronium chloride mg 5 Sodiumcarboxymethylcellulose mg 5 Syrup USP q.s. to cc 5 Dosage: 1 teaspoonful(5 cc.) every 3 to 4 hours.

EXAMPLE 33 Dry filled capsules (DFC) consisting of two sections of hardgelatin may be prepared from the following formulation:

Ingredients: In each S-3-benzo[b]thenyl isothiuronium chloride 5 mg.Lactose USP q.s.

Dosage: 1 capsule three times a day.

EXAMPLE 34 A parenteral suspension for intra-muscular administration maybe prepared in the following formulation:

Ingredients: In each S-3-benzo[b]thenyl isothiuronium chloride mg 5Isotonic solution (0.85% saline) cc 5 Surfactant (a 1% solution ofpolysorbate 8O USP) cc... 1 EXAMPLE 35 A suppository capsule may beformulated as below:

Ingredients: In each S-3-benzo[b]thenyl isothiuronium chloride 5 mg.Cocoa butter q.s.

Dosage: 1 suppository every 3 to 4 hours.

Variations can, of course, be made without departing from the spirit andscope of the invention.

What is claimed is:

1. A pharmaceutical preparation in dosage unit form adapted foradministration to obtain selective inhibition of aggressive behaviorcomprising an anti-aggression-eifective non-toxic amount within therange from about 2 to about 8 mg./kg. of body weight of a compoundselected from the group consisting of the base, 2-(3-benzo[b]thenyl)-2-thiopseudourea, or a pharmaceutically acceptable salt thereof incombination with a physiologically acceptable carrier and/ or diluenttherefor.

2. The composition of claim 1 in an orally administrable dosage form.

3. The composition of claim 2 wherein said orally administrable dosageform is a pill, tablet or capsule.

4. The composition of claim 2 wherein said orally administrable dosageform is a suspension or solution.

5. The composition of claim 4 wherein said suspension or solutioncomprises about 5 mg. of said compound per cc.

6. The composition of claim 1 in parenteral dosage form.

7. The composition of claim 6 wherein said parenteral dosage comprises asuspension or solution of about 2 mg. of said compound per 5 cc. of saidsuspension or solution.

8. The composition of claim 1 in suppository form.

9. The composition of claim 8 wherein each said suppository comprisesabout 5 mg. of said compound.

10. A method of preventing or inhibiting aggressive behavior in ananimal subject, said method comprising administering to an animalsubject characterized by the exhibition of aggressive behavior atherapeutically effective amount of the base, 2-(3benZo[b]thenyl)-2-thiopseudourea, or a pharmaceutically acceptable saltthereof.

11. The method of claim 10 wherein said compound is administered to saidanimal in an orally administrable dosage form.

12. The method of claim 11 wherein said orally administrable dosage formis a pill, tablet or capsule.

13. The method of claim 11 wherein said orally administrable dosage formis a suspension or solution.

14. The method of claim 10 wherein said compound is administered to saidanimal in parenteral dosage form.

15. The method of claim 10 wherein said compound is administered to saidanimal in rectally administrable dosage form.

16. The method of claim 15 wherein said rectally administrable dosageform is a suppository.

17. The method of claim 10 wherein said therapeutically effective amountis from about 1 to about 50 mg./kg. of body weight of said animal perday.

References Cited UNITED STATES PATENTS 3,186,990 6/1965 Lambrech et al260251 OTHER REFERENCES Cagniant, C. R., Acad. Sci. Ser. C. 1970, 271(17), 1086-1089 (Oct. 28, 1970).

STANLEY J. FRIEDMAN, Primary Examiner moose H UNKTED STATES PATENT GFFEEemmmmm @b eeRREcnoN Patent No. 3, 39,57 Dated October 1, 197

, Inventofls) Zaven S. Ariyen et a1.

It is certified that error appears in the above-ideotified patent andthat said Letters ?e cent ate hezreby eerrecte shown below:

Column 1, line 7: After inventors names and addresses,

insert assignorsto Uniroyal, Inc., New York, N'.Y.-

Signed: and sealed this 18th day of Febniary 19'.

(SEAL) Attest:

. C. MARSHALL DANN RUTH C, MASON Commissioner of" Patents AttescingOfficer and Trademarks

1. A PHARMACEUTICAL PREPARATION IN DOSAGE UNIT FROM ADAPTED FORADMINISTRATION TO OBTAIN SELECTIVE INHIBITION OF AGGRESSIVE BEHAVIORCOMPRISING AN ANTI-AGGRESSION-EFFECTIVE NON-TOXIC AMOUNT WITHIN THERANGE FROM ABOUT 2 TO ABOUT 8 MG/KG. OF BODY WEIGHT OF A COMPOUNDSELECTED FROM THE GROUP CONSISTING OF THE BASE, 2-(3-BEZO(B)THENYL)-2THIOPSEUDORUREA, OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOFIN COMBINATION WITH A PHYSIOLOCALLY ACCEPATABLE CARRIER AND/OR DILUENTTHEREFOR.